NON-HODGKIN LYMPHOMAS (NHL)– HEMATOLOGY {S1}

NON-HODGKIN LYMPHOMAS (NHL)– HEMATOLOGY {S1} BY RANJEET RAMAN

Be able to list differences (clinical, morphological) between low- and high-grade lymphomas, to describe with example how we use immunophenotyping to classify low-grade lymphomas, and to distinguish between high grade lymphomas.

Lymphomas are neoplastic proliferations of lymphoid cells in the nodes. • NHL are on the rise in the last few decades, but this is not fully explained by the AIDS epidemic. • Where leukemias are acute vs. chronic, lymphomas are high-grade vs. low-grade.

Derivation of tumor • Leukemia • Lymphoma • Immature precursor cells • Acute leukemia • High-grade lymphoma (aggressive) • (examples: lymphoblastic, Burkitt) • Mature differentiated cells • Chronic leukemia • Low-grade lymphoma (indolent) • Activated lymphocytes

Aggressive lymphoma • It is important that mature lymphocytes, unlike granulocytes in leukemia, become activated and clonally proliferate when exposed to antigen. Leukemias derived in this way are rare, but it is common in lymphomas.

There are many differences between high-grade and low-grade lymphomas: • Low-grade • High-grade • Mature lymphocytes, condensed chromatin, few nucleoli, few mitoses Immature or activated lymphocytes, open chromatin, prominent nucleoli, many mitoses Low proliferation rate High proliferation rate Cancer by over-survival (resist apoptosis) Cancer by over-proliferation Patients usually asymptomatic Systemic “B symptoms” (fever, night sweats) Indolent course Rapid aggressive course Incurable with conventional therapy Some patients may be cured with therapy

Low-Grade Lymphomas • These are derived from mature lymphocytes that resist apoptosis. Occur in adults, not children. Although they have an indolent course, they are incurable. Prototype is follicular lymphoma.Low-grade lymphomas may be followed by mycosis fungoides infections of the skin.

Follicular lymphoma • This is the most common non-Hodgkin lymphoma. It occurs in older adults. There is widespread lymphadenopathy by rarely any symptoms. May transform into high-grade lymphoma. Follicular lymphoma is incurable. • Follicular lymphoma has nodular, follicular growth that emulates normal germinal centers. These germinal centers are monotonous.

It is a neoplasm of mature B cells. • Follicular lymphoma is associated with a translocation t(14;18) that activates bcl2. This is why follicular lymphoma is a tumor of decreased apoptosis, not of proliferation.

Other low-grade lymphomas • *1. Small lymphocytic lymphoma (SLL) is identical to chronic lymphocytic leukemia (CLL)! SLL is just the nodal version, and CLL the blood version. But they are the same disease. • There is diffuse replacement of node by monotonous lymphocyte proliferation.

Lymphocytes have condensed chromatin. There are occasionally large cells that resemble aggressive lymphomas, but don’t act aggressively. Cells are CD5+.

2. Mantle cell lymphoma is an exception to earlier rules. Although the cells are mature, this is a very aggressive low-grade lymphoma and is incurable like other low-grade lymphomas. Worst of both worlds. Mantle cell lymphoma is associated with a translocation (11;14) which causes overexpression of Cyclin-D1. Cells are CD5+.

3. Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common extra nodal lymphoma. An exceptionally slow disease. Gastric MALT lymphoma is caused by H. pylori! MALT lymphoma cells appear like monocytes. CD5-.

High-Grade Lymphomas • These are derived from immature precursor lymphoid cells. They occur in all age groups, and often present with symptoms. Progress rapidly but can be cured.

Lymphoblastic lymphoma • Lymphoblastic lymphoma is the node equivalent of acute lymphocytic leukemia (ALL). One major difference, though, is that ALL is a cancer of B-precursor cells, whereas lymphoblastic lymphoma is of T-precursor cells, specifically thymic T cells. This often leads to a mediastinal mass. So lymphoblastic lymphoma = T-ALL. • Lymphoblastic lymphoma is a common childhood lymphoma.

Burkitt lymphoma • Burkitt lymphoma is associated with EBV. It often presents as a rapidly growing head/neck/jaw tumor. Sporadic Burkitt lymphoma, which is more common in the west and isn’t associated with EBV, often presents as an intestinal mass.

Burkitt lymphoma is the most rapidly proliferating cancer and is a medical emergency! It is very aggressive but can be cured with fast, aggressive therapy. • The disease produces L3 B-cell blasts, so it Burkitt lymphoma = B-ALL.

The classic Burkitt cell is the “starry sky macrophage” that is ingesting tumor debris. • Burkitt lymphoma is associated with a translocation t(8;14) that activates Myc. • Burkitt lymphoma is a very common childhood lymphoma.

Activated Cell Lymphomas – Diffuse Large B-cell Lymphoma These are aggressive lymphomas of activated mature B cells. Diffuse large B-cell lymphoma is not a distinct disease entity. It occurs when many different B cells become activated and proliferate. This may occur de novo or as endstage low-grade lymphoma.

Morphology is characterized by diffuse, not follicular expansion of very large B-cells. These large cells have open chromatin and prominent nucleoli, like high-grade lymphomas. • Diffuse large B-cell lymphoma is the most common adult non-Hodgkin lymphoma. • This has an aggressive clinical course, but half of patients can be cured

Patients usually present with symptoms in various tissues except nodes, spleen, and marrow. • Unlike low-grade lymphomas, staging is a very important prognostic factor. Also unlike low-grades, patients present with “B symptoms.” So in many ways, diffuse large B-cell lymphoma acts like a high-grade lymphoma. • This has an aggressive clinical course, but half of patients can be cured.

Diagnosis of Lymphoma • Lymphomas are clonal proliferations. Non-Hodgkin lymphomas are B-cell proliferations that express kappa or lambda light chains but not both. In T-cell proliferations, T-cell receptor gene rearrangements are used in a similar way to identify clonal expansion.

This is the basis for immunophenotyping, which is used to distinguish B from T cell lymphoma, and then to distinguish among low-grade B-cell lymphomas. • One of the main markers is CD5, a T-cell marker found on B-cells of some lymphomas • Lymphoma type • CD5 • CD10 • Cyclin D1 • MALT

Follicular lymphoma • - • + • - • SLL/CLL • + • - • - • Mantle cell lymphoma • + • - • +

NON-HODGKIN LYMPHOMAS (NHL)– HEMATOLOGY {S1}